Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons.
GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3470566?pdf=render |
| _version_ | 1818561729571848192 |
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| author | Naomi Lewin Emre Aksay Colleen E Clancy |
| author_facet | Naomi Lewin Emre Aksay Colleen E Clancy |
| author_sort | Naomi Lewin |
| collection | DOAJ |
| description | GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABA(A)-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABA(A) receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABA(A)-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABA(A)-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABA(A) reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K(+) transients can augment GABA(A)-mediated excitation, but not cause it. Our model also suggests the potential for GABA(A)-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition. |
| first_indexed | 2024-12-14T00:54:39Z |
| format | Article |
| id | doaj.art-3b40516386a54314b5dcfa5730a18845 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T00:54:39Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3b40516386a54314b5dcfa5730a188452022-12-21T23:23:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4725010.1371/journal.pone.0047250Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons.Naomi LewinEmre AksayColleen E ClancyGABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABA(A)-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABA(A) receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABA(A)-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABA(A)-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABA(A) reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K(+) transients can augment GABA(A)-mediated excitation, but not cause it. Our model also suggests the potential for GABA(A)-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition.http://europepmc.org/articles/PMC3470566?pdf=render |
| spellingShingle | Naomi Lewin Emre Aksay Colleen E Clancy Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons. PLoS ONE |
| title | Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons. |
| title_full | Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons. |
| title_fullStr | Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons. |
| title_full_unstemmed | Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons. |
| title_short | Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons. |
| title_sort | computational modeling reveals dendritic origins of gaba a mediated excitation in ca1 pyramidal neurons |
| url | http://europepmc.org/articles/PMC3470566?pdf=render |
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